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Fourteen quinolizidine derivatives, structurally related to the alkaloids lupinine and cytisine and previously studied for other pharmacological purposes, were presently tested for antiarrhythmic, and other cardiovascular effects on isolated guinea pig heart tissues in comparison to well-established reference drugs. According to their structures, the tested compounds are assembled into three subsets: (a) N-(quinolizidinyl-alkyl)-benzamides; (b) 2-(benzotriazol-2-yl)methyl-1-(quinolizidinyl)alkyl-benzimidazoles; (c) N-substituted cytisines. All compounds but two displayed antiarrhythmic activity that was potent for compounds 4, 1, 6, and 5 (in ascending order). The last compound (N-(3,4,5-trimethoxybenzoyl)aminohomolupinane) was outstanding, exhibiting a nanomolar potency (EC50 = 0.017 µM) for the increase in the threshold of ac-arrhythmia. The tested compounds shared strong negative inotropic activity; however, this does not compromise the value of their antiarrhythmic action. On the other hand, only moderate or modest negative chronotropic and vasorelaxant activities were commonly observed. Compound 5, which has high antiarrhythmic potency, a favorable cardiovascular profile, and is devoid of antihypertensive activity in spontaneously hypertensive rats, represents a lead worthy of further investigation.

Diterpenoid alkaloids, originating from the amination of natural tetracyclic diterpenes, have long interested scientists due to their medicinal uses and infamous toxicity which has limited the clinical application of the native compound. Alkaloid lappaconitine extracted from various Aconitum and Delphinium species has displayed extensive bioactivities and active ongoing research to reduce its adverse effects. A convenient route to construct hybrid molecules containing diterpenoid alkaloid lappaconitine and 3H-1,5-benzodiazepine fragments was proposed. The key stage involved the formation of 5′-alkynone-lappaconitines in situ by acyl Sonogashira coupling of 5′-ethynyllappaconitine, followed by cyclocondensation with o-phenylenediamine. New hybrid compounds showed low toxicity and outstanding analgesic activity in experimental pain models, which depended on the nature of the substituent in the benzodiazepine nucleus. An analogous dependence was also shown for the antiarrhythmic activity in the epinephrine arrhythmia test in vivo. Studies on the isolated atrium have shown that the mechanism of action of the new compounds is included the blockade of beta-adrenergic receptors and potassium channels. Molecular docking analysis was conducted to determine the binding potential of target molecules with the voltage-gated sodium channel NaV1.5. All obtained results provide a basis for future rational modifications of lappaconitine, reducing side effects, while retaining its therapeutic effects.

Cardiovascular diseases (CVDs) are the leading cause of death worldwide, with cardiac arrhythmias being one of the main factors contributing to morbidity. Currently, several established antiarrhythmic medications with proven efficacy are available. However, frequent use of these medications causes adverse effects with medium- and long-term use. This necessitates the development of new medications, preferably of natural origin and with ethnopharmacological relevance. In this sense, Acmella oleracea presents itself as an alternative for the treatment of arrhythmia, considering studies suggesting its cardioprotective effect. Therefore, the objective of this study was to evaluate the electrophysiological and antiarrhythmic effects of a supercritical extract of Acmella oleracea (SEAO) in rats. The extract was obtained by supercritical CO2 extraction at 70 °C and 320 bar, with an extract yield of 9.72 ± 0.26% (db) and a spilanthol yield of 25.91%. The extract was administered intraperitoneally at doses of 10, 15, and 20 mg/kg in two experimental models: (1) assessment of cardiac electrophysiology and (2) epinephrine-induced arrhythmia. Electrocardiogram (ECG) parameters were measured and compared with controls treated with epinephrine and lidocaine. The SEAO group maintained sinus rhythm and preserved cardiac intervals, with a significant reduction in heart rate and R-R interval compared to the epinephrine group. These findings demonstrate that SEAO exerts dose-dependent antiarrhythmic effects comparable to those of lidocaine. The results corroborate the potential use of SEAO as a natural alternative for arrhythmia management, encouraging further pharmacological and clinical studies.

Four phenylcarbamic acid derivatives, (1-(4-fluorophenyl)- 4-[3-(4-methoxyphenylcarbamoyloxy)-2-hydroxypropyl]piperazinium chloride (1), (1-(2-methylphenyl)-4-[3-(4-methoxyphenylcarbamoyloxy)- 2-hydroxypropyl]piperazinium chloride) (2), (1-(2-methylphenyl)-4-[3-(4-ethoxyphenylcarbamoyloxy)- 2-hydroxypropyl]piperazinium chloride) (3) and (1-(3-trifluoromethylphenyl)-4-[3-(4-methoxyphenylcarbamoyloxy)- 2-hydroxypropyl]piperazinium chloride) (4) were investigated for their ability to affect various cardiovascular functions and to establish their chemical structure-biological activity relationship. The compounds were evaluated for their antiarrhythmic efficacy using ouabain-induced rhythm disturbances and the ability to inhibit the positive chronotropic effect of isoproterenol in isolated atria of Wistar rats. Electrocardiogram (ECG) parameters in isolated hearts of spontaneously hypertensive rats (SHR) perfused according to the Langendorff method and ability to decrease phenylephrine- -induced contraction of the aortic strips after repeated administration of the compounds were also analyzed. Only compound 3 delayed significantly the evaluated parameter of arrhythmogenicity and was able to antagonize the isoproterenol- induced positive chronotropic effect in normotensive rats’ atria. Similarly, in SHR rats, only compound 3 was able to decrease heart frequency significantly without influencing the duration of QT (time between the start of the Q wave and the end of the T wave) and QTc (frequency corrected QT) intervals. The evaluated endothelial function was improved after administration of compound 2. Fluorine-containing structures (1 and 4) were less effective compared to 2´-methylphenylpiperazine derivatives (2 and 3). The latter two compounds showed suitable efficacy, which supported their use for futher pharmacological research.

Acetaminophen, also known as APAP or paracetamol, is one of the most widely used analgesics (pain reliever) and antipyretics (fever reducer). According to the U.S. Food and Drug Administration, currently there are 235 approved prescription and over-the-counter drug products containing acetaminophen as an active ingredient. When used as directed, acetaminophen is very safe and effective; however when taken in excess or ingested with alcohol hepatotoxicity and irreversible liver damage can arise. In addition to well known use pain relief and fever reduction, recent laboratory and pre-clinical studies have demonstrated that acetaminophen may also have beneficial effects on blood glucose levels, skeletal muscle function, and potential use as cardioprotective and neuroprotective agents. Extensive laboratory and pre-clinical studies have revealed that these off-label applications may be derived from the ability of acetaminophen to function as an antioxidant. Herein, we will highlight these novel applications of acetaminophen, and attempt, where possible, to highlight how these findings may lead to new directions of inquiry and clinical relevance of other disorders.

We studied the antiarrhythmic activity of novel sterically hindered phenols – 4-methyl-2,6- diisobornylphenol (dibornol) in acute myocardial ischemia/reperfusion in male Wistar rats. Left coronary artery occlusion (10 min) in control group induced different ventricular arrhythmia and 23% mortality of animals. Dibornol (p.o. administration 100 mg/kg 24 and 3 hours before ischemia) did not change the frequency and kinds of arrhythmia in acute ischemia, but significantly reduced the frequency and the level of seriousness of arrhythmia in the reperfusion period, decreased the mortality of rats due to lethal arrhythmia.

We studied anti-ischemic activity of n -tyrozol under conditions of repeated transient myocardial ischemia in rats caused by repeated (5×3 min) occlusion of the left coronary artery. n -Tyrozol administered intraperitoneally in a dose of 20 mg/kg daily over 4 days before the ischemia modeling (the last injection 15 min prior to the start of the experiment) produced a clear-cut anti-ischemic effect: it reduced ST elevation and promoted more complete recovery of ECG during reperfusion. During reperfusion periods, n -tyrozol significantly decreased the risk of ventricular fibrillation and shortened the duration of tachyarrhythmia episodes (ventricular tachycardia and fibrillation).

Using the SARD-21 (Structure Activity Relationship & Design) computer system, structural features of high- and low-effective antiarrhythmic agents have been recognized and the influence of these features on the antiarrhythmic properties has been evaluated. This information has been used for generation of the model to predict antiarrhythmic effectiveness of pharmaceutical preparations at the recognition level of 82% by means of two different approaches. The recognized structural parameters may be successfully used to design new highly effective antiarrhythmic drugs, and also to modify structures of the already-existing anti-arrhythmic drugs in order to increase the effectiveness of their antiarrhythmic action.

Estrone, estriol, and estradiol valerate exhibited antiarrhythmic activity in rats with aconitine-induced arrhythmia. Estrone was most effective in this respect.Estrone, estriol, and estradiol valerate exhibited antiarrhythmic activity in rats with aconitine-induced arrhythmia. Estrone was most effective in this respect.